Our understanding of the mechanism of pathogenesis induced by HIV remains limited by the difficulty of conducting mechanistic studies in humans. Availability of a small animal model system that faithfully reproduces the viral pathogenic effects and the host anti-viral immune response observed in humans would significantly advance our understanding of HIV pathogenesis and would facilitate development of new approaches to block viral replication and to elicit neutralizing immune responses. Until recently, infection of murine cells with HIV has not been achievable because of a species-specific block at the level of viral entry. This restriction has been overcome with the discovery of chemokine receptor family members that function with CD4 as receptors for HIV and SIV. We have prepared mice that express human CD4 and human CCR5 or CXCR4 in T cells and macrophages, and have shown that their T cells can be infected with viruses pseudotyped with HIV and SIV envelope glycoproteins. However, other species-specific restrictions at several stages of the retroviral replication cycle currently limit the utility of this murine model. One of these restrictions, at the level of Tat transcriptional transactivation, can now at least be partially overcome, by expressing the human cyclin T gene in murine cells. We propose to introduce the human cyclin T gene into the germ line of mice that already express the human receptors for HIV and determine if this further facilitates viral replication in mice (Specific Aim 1). We will also develop approaches for infecting the genetically modified mice and for propagating HIV and/or SIV in vivo (Specific Aim 2). These approaches will emphasize the likely critical role of dendritic cells in potentiation of T cell infection both in vitro and in vivo. Expression cloning approaches, some of which we have already developed, will be used to identify new human genes that are involved in the HIV replication cycle and whose introduction into mice may further improve the model (Specific Aim 3). These aims constitute only the first steps towards building a useful mouse model, and are unlikely to provide a pathogenesis model in the short term. However, in vitro studies have suggested that the interaction of HIV envelope glycoprotein with the receptor complex consisting of CD4 and chemokine receptor results in signal transduction and impaired T cell function or even cell death. We will, therefore, determine if soluble gp120 or cell surface-bound gp120/gp41 influence T cell development and function in mice that express the human viral receptor complex (Specific Aim 4). This analysis may provide important insight into the mechanism of immunodeficiency, and will thus guide future studies using this animal model system.